In adult T cell leukemia/lymphoma (ATL), a plurality of genetic abnormalities are accumulated in HTLV-1 infected peripheral blood T cells during a long latent period of 50 to 60 years, which can cause malignant transformation. It is presumed that there are 20 million or more human adult T-cell leukemia virus type I (HTLV-1) infected persons (carriers) in the world, and it is presumed that there are 1.08 million or more infected persons, and ATL develops in about 1200 persons every year in Japan (Non Patent Literature 1). It has been revealed, as a result of cohort study, that ATL develops only in carriers in which a ratio of HTLV-1 infected cells in peripheral blood (provirus load, PVL) is 4% or more (Non Patent Literature 2). This group of persons with high risk of development occupies 25% in the entire carriers, and it is expected that reduction of the number of infected cells would lead to reduction of risk of the ATL development. There are, however, a large number of unclear points in molecular mechanisms of immortalization and tumorigenesis of cells caused by HTLV-1 and of refractoriness, and there has been found neither an effective method for treating ATL nor a method for selectively removing infected cells. Owing to appearance of an anti-CCR4 antibody, that is, a molecular target drug against ATL, the treatment outcome has been improved, but the prognosis is still the worst among those of malignant lymphomas (Non Patent Literature 3), and in terms of median survival, the treatment outcome of chemotherapy for acute ATL is 12.7 months (Non Patent Literature 4) and the treatment outcome by the CCR4 antibody against recurrence is 13.7 months (Non Patent Literature 5). Accordingly, it is imperative, based on medical condition elucidation at the molecular level, to prevent the virus infection, to prevent the leukemia development and to develop a novel treatment method.
It has been revealed, as a result of large scale analysis of gene expression using a large number of ATL clinical samples, that ATL cells are a population having a very uniform and abnormal gene expression pattern (Non Patent Literature 6). Besides, ATL cells have characteristic signal transduction system abnormality, which corresponds to a key of survival and growth of tumor cells, and it has been revealed that the abnormality is derived from accumulation of epigenetic abnormalities (Non Patent Literature 7).
The polycomb family negatively controls gene expression through chromatin control by histone modification. Enhancer of Zeste Homologue 1/2 (EZH1/2) corresponds to active center of Polycomb Repressive Complex 2 (PRC2) that trimethylates histone H3K27. EZH1 and EZH2 retain an epigenome in a cell while mutually compensating their functions. Inhibition of EZH2 leads to reduction of methylation level of H3K27 throughout the cell, but this effect is restricted by the compensating effect of EZH1. When EZH1 and EZH2 are simultaneously inhibited, the methylation can be more effectively eliminated (Non Patent Literature 8). It has been found that abnormality in a PRC2 component leads to cancer or abnormality in stem cell function, and in particular, accumulation of methylated H3K27me3 induced by gene abnormality or increased expression of EZH2 is identified in a large number of cancers, and earnest studies are being conducted mainly for EZH2 as a novel cancer molecular target drug (Non Patent Literatures 9 and 10).
The abnormality of polycomb family occurring in ATL was cleared by exhaustive gene expression analysis (Non Patent Literatures 6 and 11). In particular, overexpression of EZH2 is conspicuous, and increase of the methylation level of H3K27 in the entire cells is also detected. Besides, it has been cleared that EZH2-dependent inhibition of miR-31 results in expression of NF-κB Inducing Kinase (NIK) so as to constitutively activate NF-κB pathway, and hence, EZH2 is regarded as effective as a molecular target drug against ATL.